<p>List of Contributors xx</p> <p>Preface xxvi</p> <p>Acknowledgements xxvii</p> <p><b>PART I 1</b></p> <p>1 Introduction 3<br /> <i>Saura C. Sahu</i></p> <p>References 4</p> <p>2 Application of Stem Cells and iPS Cells in Toxicology 5<br /> <i>Maria Virginia Caballero, Ramon A. Espinoza</i><i>‐</i><i>Lewis, and Manila Candiracci</i></p> <p>2.1 Introduction 5</p> <p>2.2 Significance 6</p> <p>2.3 Stem Cell (SC) Classification 7</p> <p>2.4 Stem Cells and Pharmacotoxicological Screenings 8</p> <p>2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 8</p> <p>2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 9</p> <p>2.7 Mesenchymal Stem Cells (Adult Stem Cells) 10</p> <p>2.8 Hematopoietic Stem Cells (Adult Stem Cells) 11</p> <p>2.9 Cardiotoxicity 12</p> <p>2.10 Hepatotoxicity 15</p> <p>2.11 Epigenetic Profile 17</p> <p>2.12 Use of SC and iPSC in Drug Safety 18</p> <p>2.13 Conclusions and Future Applications 19</p> <p>Acknowledgments 19</p> <p>References 19</p> <p><b>3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26<br /> </b><i>Harish K Handral, Gopu Sriram, and Tong Cao</i></p> <p>3.1 Introduction 26</p> <p>3.2 Stem Cells 27</p> <p>3.3 High Throughput Screening (HTS) 31</p> <p>3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 37</p> <p>3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 38</p> <p>3.6 Conclusion 40</p> <p>Acknowledgement 41</p> <p>Disclosure Statement 41</p> <p>Author’s Contribution 41</p> <p>References 41</p> <p><b>4 Human Pluripotent Stem Cells for Toxicological Screening 50<br /> </b><i>Lili Du and Dunjin Chen</i></p> <p>4.1 Introduction 50</p> <p>4.2 The Biological Characteristics of hPSCs 51</p> <p>4.3 Screening of Embryotoxic Effects using hPSCs 52</p> <p>4.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 55</p> <p>4.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 60</p> <p>4.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 62</p> <p>4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65</p> <p>Acknowledgments 66</p> <p>References 67</p> <p><b>5 Effects of Culture Conditions on Maturation of Stem Cell</b><b>‐</b><b>Derived Cardiomyocytes 71<br /> </b><i>Deborah K. Hansen, Amy L. Inselman, and Xi Yang</i></p> <p>5.1 Introduction 71</p> <p>5.2 Lengthening Culture Time 75</p> <p>5.3 Substrate Stiffness 76</p> <p>5.4 Structured Substrates 78</p> <p>5.5 Conclusions 82</p> <p>Disclaimer 82</p> <p>References 83</p> <p><b>6 Human Stem Cell</b><b>‐</b><b>Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85<br /> </b><i>Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary</i></p> <p>6.1 Introduction 85</p> <p>6.2 Overview of hPSC‐Derived Cardiomyocytes 88</p> <p>6.3 Human PSC‐CM Models for Cardiotoxicity Investigations 90</p> <p>6.4 Conclusions and Future Direction 112</p> <p>References 112</p> <p><b>7 Disease</b><b>‐</b><b>Specific Stem Cell Models for Toxicological Screenings and Drug Development 122<br /> </b><i>Matthias Jung, Juliane</i><i>‐</i><i>Susanne Jung, Jovita Schiller, and Insa S. Schroeder</i></p> <p>7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 122</p> <p>7.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 127</p> <p>7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 132</p> <p>7.4 Stem Cell Models for Toxicological Screenings of EDCs 133</p> <p>References 135</p> <p><b>8 Three</b><b>‐</b><b>Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145<br /> </b><i>Ran</i><i>‐</i><i>Ran Zhang, Yun</i><i>‐</i><i>Wen Zheng, and Hideki Taniguchi</i></p> <p>8.1 Introduction 145</p> <p>8.2 Hepatic Cell Lines and Primary Human Hepatocytes 146</p> <p>8.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 147</p> <p>8.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 148</p> <p>8.5 In Vivo: Humanized Liver Models 149</p> <p>8.6 Summary 150</p> <p>Acknowledgments 150</p> <p>References 150</p> <p><b>9 Utilization of In Vitro Neurotoxicity Models in Pre</b><b>‐</b><b>Clinical Toxicity Assessment 155<br /> </b><i>Karin Staflin, Dinah Misner, and Donna Dambach</i></p> <p>9.1 Introduction 155</p> <p>9.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 159</p> <p>9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 162</p> <p>9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 167</p> <p>9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 170</p> <p>9.6 Concluding Remarks 172</p> <p>References 172</p> <p><b>10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179<br /> </b><i>R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi</i></p> <p>10.1 Introduction 179</p> <p>10.2 General Features of Placental Structure 180</p> <p>10.3 The Human Placenta 180</p> <p>10.4 Human Placental Cells in Toxicology Research 182</p> <p>10.5 Placental Trophoblast Derived from hESC 183</p> <p>10.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 185</p> <p>10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 185</p> <p>10.8 Concluding Remarks 191</p> <p>Acknowledgments 192</p> <p>References 192</p> <p><b>11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196</b></p> <p><i>Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell</i></p> <p>11.1 Mesenchymal Stem Cells 196</p> <p>11.2 Endocrine Disruptors 198</p> <p>11.3 Pesticides 201</p> <p>11.4 Alkyl Phenols and Derivatives 206</p> <p>11.5 Bisphenol A 211</p> <p>11.6 Polychlorinated Biphenyls 216</p> <p>11.7 Phthalates 221</p> <p>11.8 Areas for Future Research 225</p> <p>11.9 Conclusions 226</p> <p>Abbreviations 226</p> <p>References 228</p> <p><b>12 Epigenetic Landscape in Embryonic Stem Cells 238<br /> </b><i>Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang</i></p> <p>12.1 Introduction 238</p> <p>12.2 DNA Methylation in ESCs 239</p> <p>12.3 Histone Methylation in ESCs 240</p> <p>12.4 Chromatin Remodeling and ESCs Regulation 241</p> <p>12.5 Concluding Remarks 242</p> <p>Acknowledgements 243</p> <p>References 243</p> <p><b>PART II 247</b></p> <p><b>13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249<br /> </b><i>Kevin G. Chen</i></p> <p>13.1 Introduction 249</p> <p>13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 250</p> <p>13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 251</p> <p>13.4 Diverse hPSC Culture Platforms for Drug Discovery 252</p> <p>13.5 Representative Analyses of hPSC‐Based Drug Discovery 255</p> <p>13.6 Current Challenges and Future Considerations 257</p> <p>13.7 Concluding Remarks 260</p> <p>Acknowledgments 260</p> <p>References 260</p> <p><b>14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265<br /> </b><i>H. Rashidi and D.C. Hay</i></p> <p>14.1 Introduction 265</p> <p>14.2 Traditional Scaffold‐Based Tissue Engineering 266</p> <p>14.3 Scaffold‐Free 3D Culture Systems 269</p> <p>14.4 Modular Biofabrication 270</p> <p>14.5 3D Bioprinting 270</p> <p>14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 272</p> <p>14.7 Applications in Drug Discovery and Toxicity 275</p> <p>14.8 Conclusions 278</p> <p>References 278</p> <p><b>15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288<br /> </b><i>Juliann G. Kiang</i></p> <p>15.1 Introduction 288</p> <p>15.2 MSC Characterization 289</p> <p>15.3 MSCs and Tissue or Organ Therapy 293</p> <p>15.4 Conclusions 298</p> <p>Acknowledgments 298</p> <p>References 298</p> <p><b>16 Stem Cell Therapeutics for Cardiovascular Diseases 303<br /> </b><i>Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang,</i></p> <p><i>and Chunying Li</i></p> <p>16.1 Introduction 303</p> <p>16.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 304</p> <p>16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 306</p> <p>16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 306</p> <p>16.5 Concluding Remarks 315</p> <p>Acknowledgments 316</p> <p>References 316</p> <p><b>17 Stem</b><b>‐</b><b>Cell</b><b>‐</b><b>Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324<br /> </b><i>David M Smadja and Jean</i><i>‐</i><i>Sébastien Silvestre</i></p> <p>17.1 Sources of Stem Cells for Vascular Regeneration 325</p> <p>17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 329</p> <p>17.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333</p> <p>References 337</p> <p><b>18 Gene Modified Stem/Progenitor</b><b>‐</b><b>Cell Therapy for Ischemic Stroke 347<br /> </b><i>Yaning Li, Guo</i><i>‐</i><i>Yuan Yang, and Yongting Wang</i></p> <p>18.1 Introduction 347</p> <p>18.2 Gene Modified Stem Cells for Ischemic Stroke 348</p> <p>18.3 Gene Transfer Vectors 354</p> <p>18.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 356</p> <p>18.5 Conclusion 356</p> <p>Abbreviations 356</p> <p>Acknowledgments 357</p> <p>References 357</p> <p><b>19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363<br /> </b><i>Pengyu Huang, Bin Li, and Yun</i><i>‐</i><i>Wen Zheng</i></p> <p>19.1 Introduction 363</p> <p>19.2 GI Development and Regeneration 365</p> <p>19.3 GI Tumorigenesis and Stemness Gene Expression 367</p> <p>19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 368</p> <p>19.5 Summary and Perspective 369</p> <p>Acknowledgments 369</p> <p>References 370</p> <p><b>20 Cancer Stem Cells: Concept, Significance, and Management 375</b></p> <p><i>Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh</i></p> <p>20.1 Introduction 375</p> <p>20.2 Stem Cells and Cancer: Historical Perspective 376</p> <p>20.3 Cancer Stem Cells 377</p> <p>20.4 Identification and Isolation of CSCs 382</p> <p>20.5 Pathological Significance of Cancer Stem Cells 388</p> <p>20.6 Pathways Regulating Cancer Stem Cells 389</p> <p>20.7 Therapeutic Strategies Targeting Cancer Stem Cells 394</p> <p>20.8 Conclusion and Future Directions 399</p> <p>References 400</p> <p><b>21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414<br /> </b><i>Joanna Triscott and Sandra E. Dunn</i></p> <p>21.1 Brain Tumor Cancer Stem Cells 414</p> <p>21.2 Medulloblastoma 416</p> <p>21.3 Hijacking Cerebellar Development 417</p> <p>21.4 Molecular Classification of MB 420</p> <p>21.5 Mouse Models and Cell of Origin 424</p> <p>21.6 Additional Drivers of MB 425</p> <p>21.7 Repurposing Off‐Patent Drugs 426</p> <p>21.8 Emerging Therapies for MB 428</p> <p>21.9 Conclusion 429</p> <p>Acknowledgments 429</p> <p>References 429</p> <p><b>22 Induced Pluripotent Stem Cell</b><b>‐</b><b>Derived Outer-Blood</b><b>‐</b><b>Retinal Barrier for Disease Modeling and Drug Discovery 436<br /> </b><i>Jun Jeon, Nathan Hotaling, and Kapil Bharti</i></p> <p>22.1 Introduction 436</p> <p>22.2 The Outer Blood‐Retinal Barrier 437</p> <p>22.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 439</p> <p>22.4 iPSC Based OBRB Disease Models 442</p> <p>22.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 448</p> <p>22.6 Conclusion and Future Directions 451</p> <p>References 451</p> <p><b>23 Important Considerations in the Therapeutic Application of Stem Cells in Bone</b></p> <p><b>Healing and Regeneration 458<br /> </b><i>Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar</i></p> <p>23.1 Introduction 458</p> <p>23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 459</p> <p>23.3 Scaffolds 461</p> <p>23.4 Animal Models in Bone Healing and Regeneration 464</p> <p>23.5 Conclusions and Future Directions 472</p> <p>References 472</p> <p><b>24 Stem Cells from Human Dental Tissue for Regenerative Medicine 481<br /> </b><i>Junjun Liu and Shangfeng Liu</i></p> <p>24.1 Introduction 481</p> <p>24.2 Dental Stem Cells 482</p> <p>24.3 Potential Clinical Applications 488</p> <p>24.4 Safety 492</p> <p>24.5 Dental Stem Cell Banking 493</p> <p>24.6 Conclusions and Perspective 494</p> <p>References 495</p> <p><b>25 Stem Cells in the Skin 502<br /> </b><i>Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu</i></p> <p>25.1 Introduction 502</p> <p>25.2 Stem Cells in the Skin 503</p> <p>25.3 Isolation and the Biological Markers of Skin Stem Cells 506</p> <p>25.4 Skin Stem Cell Niches 508</p> <p>25.5 Signaling Control of Stem Cell Differentiation 510</p> <p>25.6 Stem Cells in Skin Aging 514</p> <p>25.7 Stem Cells in Skin Cancer 516</p> <p>25.8 Medical Applications of Skin Stem Cells 518</p> <p>25.9 Conclusions and Future Directions 520</p> <p>References 521</p> <p>Author Index 527</p> <p>Subject Index 529</p>